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. 2021 Aug;51(8):2006-2026.
doi: 10.1002/eji.202048900. Epub 2021 May 29.

c-Rel employs multiple mechanisms to promote the thymic development and peripheral function of regulatory T cells in mice

Thomas S Fulford  1 , Raelene Grumont  1 , Rushika C Wirasinha  1 , Darcy Ellis  1 , Adele Barugahare  1   2 , Stephen J Turner  1   3 , Haroon Naeem  2 , David Powell  2 , Paul A Lyons  4   5 , Kenneth G C Smith  4   5 , Sebastian Scheer  1 , Colby Zaph  1 , Ulf Klein  6 , Stephen R Daley  1 , Steve Gerondakis  1
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Free article

c-Rel employs multiple mechanisms to promote the thymic development and peripheral function of regulatory T cells in mice

Thomas S Fulford et al. Eur J Immunol. 2021 Aug.
Free article

Abstract

The NF-κB transcription factor c-Rel is a critical regulator of Treg ontogeny, controlling multiple points of the stepwise developmental pathway. Here, we found that the thymic Treg defect in c-Rel-deficient (cRel-/- ) mice is quantitative, not qualitative, based on analyses of TCR repertoire and TCR signaling strength. However, these parameters are altered in the thymic Treg-precursor population, which is also markedly diminished in cRel-/- mice. Moreover, c-Rel governs the transcriptional programme of both thymic and peripheral Tregs, controlling a core of genes involved with immune signaling, and separately in the periphery, cell cycle progression. Last, the immune suppressive function of peripheral cRel-/- tTregs is diminished in a lymphopenic model of T cell proliferation and is associated with decreased stability of Foxp3 expression. Collectively, we show that c-Rel is a transcriptional regulator that controls multiple aspects of Treg development, differentiation, and function via distinct mechanisms.

Keywords: Cell cycle progression; Regulatory T cells; Thymic development; c-Rel.

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